tbuckley/cabot-search huggingface dataset:
Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM)
Authors: A. Hauschild, A. M. Eggermont, E. Jacobson, S. J. O'Day
Journal: Journal of Clinical Oncology (2009)

LBA9012 Background: Elesclomol is an investigational first-in-class oxidative stress inducer that increases oxidative stress in cancer cells leading to mitochondria-induced apoptosis. Methods: Patients (pts) with Stage IV MM, no prior chemotherapy, LDH μ 2× ULN were randomized (1:1) to either 213 mg/m2 elesclomol in combination with 80 mg/m2 paclitaxel (ELPAC) or 80 mg/m2 paclitaxel alone (P); both were given weekly ×3 followed by 1 week rest until disease progression. Pts were stratified by prior non-cytotoxic treatment, M1 grade, and LDH. The primary endpoint was PFS with >90% power to detect a 2-month improvement. The primary PFS analysis was planned once all pts had been enrolled and at least 164 PFS events had occurred. Results: 651 pts were enrolled between September 2007 and February 2009. Prognostic factors were generally well balanced. PFS analysis was based on investigator assessment of 411 pts (219 events). Median PFS was 3.5 m (95% CI 2.7–3.7) in ELPAC and 1.9 m (95% CI 1.9–3.3) in P [HR 0.88; 95% CI 0.67–1.16, p=0.3695]. The median number of cycles was 3 in ELPAC and 2 in P. Safety analysis showed increased signals on ELPAC including increased ≥Gr 3 AEs (N=405, 32.8% vs. 23.5%), increased AEs leading to death (N=405, 3.5% vs <1%) and increased overall deaths (N=651, 80 vs 53; 80% censored). Most common AEs in ELPAC were fatigue (32.8%), alopecia (31.3%) and nausea (27.9%). Conclusions: There was an improvement in PFS in the ELPAC arm, but it did not achieve statistical significance. In February 2009, the study was halted based on the recommendation of the DMC to unblind the study after the DMC observed increased deaths on the ELPAC arm. The DMC could not determine whether the observed increased deaths were treatment related or not. Of note, in this analysis there were no specific target organ toxicities attributable to ELPAC that could explain the imbalance of deaths. OS data continues to be collected to determine if the observed imbalance in OS persists as the data mature. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta
Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts
Authors: Hiroaki Seto, Satoshi Kamekura, Toshiki Miura, Aiichiro Yamamoto, Hirotaka Chikuda, Toru Ogata, Hisatada Hiraoka, Hiromi Oda, Kozo Nakamura, Hisashi Kurosawa, Ung-il Chug, Hiroshi Kawaguchi, Sakae Tanaka
Journal: Journal of Clinical Investigation (2004)

The role of TGF-β/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector–mediated gene transduction system. Expression of constitutively active activin receptor–like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.
THE BUBBLE SIGN. A NEW TRACK TO DETECT A PERFORATION AFTER COLD SNARE POLYPECTOMY
Authors: R Sánchez Joaquín, M Sánchez Alonso, M Pellise Urquiza
Journal: Endoscopy (2019)

Cold snare polypectomy (CSP) is nowadays a highly recommended procedure for treatment of sessile adenomas up to 10 mm in size. Despite this procedure is not widely accepted in larger lesions, prospective and retrospective studies show outstanding results in terms of efficacy and safety, even performing piecemeal resection (wide field CSP). Indeed, in two recent meta-analysis no perforations have been described with this technique.
Promising Therapy for Bone Marrow Failure from Myelodysplastic Syndromes
Journal: Annals of Internal Medicine (2002)

Summaries for Patients6 August 2002Promising Therapy for Bone Marrow Failure from Myelodysplastic SyndromesSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-137-3-200208060-00003 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail What is the problem and what is known about it so far?Bone marrow makes blood cells, including red blood cells, white blood cells, and platelets. In some older persons, there is a problem with the bone marrow in which the marrow cannot make new blood cells effectively (myelodysplastic syndromes). These persons get low numbers of red blood cells (anemia), white blood cells (neutropenia), or platelets (thrombocytopenia). Low numbers of red blood cells and platelets require frequent transfusions to prevent tiredness, shortness of breath, and bleeding. Low numbers of white blood cells lead to infections and a frequent need for ... Author, Article, and Disclosure InformationAffiliations: The summary below is from the full report titled “Antithymocyte Globulin for Treatment of the Bone Marrow Failure Associated with Myelodysplastic Syndromes.” It is in the 6 August 2002 issue of Annals of Internal Medicine (volume 137, pages 156-163). The authors are JJ Molldrem, E Leifer, E Bahceci, Y Saunthararajah, M Rivera, C Dunbar, J Liu, R Nakamura, NS Young, and AJ Barrett.Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAntithymocyte Globulin for Treatment of the Bone Marrow Failure Associated with Myelodysplastic Syndromes Jeffrey J. Molldrem , Eric Leifer , Erkut Bahceci , Yogen Saunthararajah , Mary Rivera , Cynthia Dunbar , Johnson Liu , Riotoro Nakamura , Neal S. Young , and A. John Barrett Metrics 6 August 2002Volume 137, Issue 3Page: I-27KeywordsBlood cellsBone marrowBone marrow failureGlobulinsHemorrhageMyelodysplastic syndromesPatientsPlateletsRed blood cellsWhite blood cells ePublished: 6 August 2002 Issue Published: 6 August 2002 Copyright & PermissionsCopyright © 2002 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
06.12 New protein array technology identifies rituximab treated non responder rheumatoid arthritis patients are generating a new autoantibody repertoire
Authors: Zoltan Konthur, Melvin M Wiemkes, Thomas Häupl, Gerd R Burmester, Karl Skriner
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rituximab (RTX) has shown clinical efficacy but up to 40% of RTX treated rheumatoid arthritis (RA) patients are poor responders (Ann-Rheum-Dis. 2005 Feb;64 (2):246–52) and the commonly used RA biomarkers (<i>RF/ACPA)</i> are poor predictors for therapy response. In this study the autoantibody repertoire analysed on protein macorarrays from RA patients under RTX treatment was correlated to clinical DAS28 response. <h3>Methods</h3> Screening of RA sera was conducted on 37.830 unique human proteins on protein marcoarrays (http://www.engine-gmbh.de) with sera taken before and 24 weeks after treatment. The autoantibody response of different immunoglobulin classes IgD, IgA, and IgG was recorded and bioinformatically evaluated. Response was determined according to DAS28 criteria. DAS 28 scores in the responder group before treatment was from 5.4–7.8 and in the non-responder group 5,6–6,8. We analysed 26 RA patient sera (9 responder, 7 non-responder and 10 patients with blinded response classification) investigated the data of found autoantigens <i>in-silico</i> and by hierarchical clustering. <h3>Results</h3> In the cohort of 26 patients 1292 different autoantigens (IgD,IgA,IgG) were detected. Using protein array we investigated clusters of autoantigen responses that disappeared or developed during RTX treatment of RA patients. RA autoantigenic patterns before and 6 month after RTX treatment were patient-specific and no relevant autoantigenic cluster was found that was shared between patients or associated with response. However, RTX reduced the repertoire of autoantibodies after 24 weeks of treatment in the tested RA patient cohort on average by 60%. RA patients which do not respond are generating on average 63% new autoantibodies. In good responders to RTX only 5,5% (+/-3%) new autoantibodies can be detected. The IgA and IgG autoantibody repertoire in the serum after 24 weeks of RTX treatment is reduced (IgA: 41%, IgG :31%) in good responders whereas it is increased (IgA: 1,3%, IgG: 24%) in non responders to RTX. <h3>Conclusion</h3> After 6 month of RTX treatment the autoantibody repertoire in all good responding RA patients is reduced and non responders to RTX change their autoantibody repertoire directed against new but patient specific antigens. The fast rebuilding of functional B cells is only detected in non-responders to rituximab.
Abstract LB-085: <i>PTPN11</i> plays oncogenic roles and is a therapeutic target for <i>BRAF</i> wild-type melanomas
Authors: Kristen Hill, Jane Messina, Jie Wu, Charles E. Chalfant, Minjung Kim
Journal: Cancer Research (2019)

Abstract Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11 E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11 E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRAS Q61K-mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for BRAF wild-type melanoma. Citation Format: Kristen Hill, Jane Messina, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-085.
Health fraud's toll: lost hopes, misspent billions
Authors: V. S. Cowart
Journal: JAMA (1988)

THE LINEUP of worthless health devices and potions displayed at the recent National Health Fraud Conference in Kansas City, Mo, would have been almost humorous if it didn't represent the lost dreams, desperate hopes, and misspent cash of so many Americans. Medical quackery perpetrated against the public costs some $25 billion a year—no laughing matter—with phony cancer cures alone accounting for $4 billion to $5 billion of that amount. The elderly spend $10 billion a year on medical quackery. But youngsters are a promising market for false claims that often capitalize on the desire to look better, such as by losing weight. And some quackery cuts across age groups. For example, arthritis affects about one in seven Americans, and the "miracle" cures range from the relatively harmless, like lemon juice or milk from "specially treated" cows, to the potentially dangerous unsupervised use of corticosteroids. The conference focused attention on the
Massachusetts Medical Society
Authors: John B. Skinner
Journal: New England Journal of Medicine (1957)

GILBERT HORRAX (1887–1957)With the death of Gilbert Horrax on September 28, 1957, in Boston, the special field of neurosurgery lost one of its most ardent disciples.Horrax's position was unique, for he was intimately connected with the development of this special branch of surgical treatment almost from its beginning when Harvey Cushing began to specialize at the Johns Hopkins Hospital. Even before he graduated as a Doctor of Medicine from the Johns Hopkins University School of Medicine in 1913, Horrax had already become an admirer of Cushing and possibly was also attracted to Cushing's operating room because of the . . .
Study design
Authors: P. Sedgwick
Journal: BMJ (2009)

In the dentate gyrus (DG) of the adult mouse hippocampus, a substantial number of new cells are generated daily, but only a subset of these survive and differentiate into mature neurons, whereas the majority undergo programmed cell death (PCD). However, neither the intracellular machinery required for adult stem cell-derived neuronal death nor the biological implications of the significant loss of these newly generated cells have been examined. Several markers for apoptosis failed to reveal cell death in Bax-deficient mice, and this, together with a progressive increase in neuron number in the DG of the Bax knock-out, indicates that Bax is critical for the PCD of adult-generated hippocampal neurons. Whereas the proliferation of neural progenitor cells was not altered in the Bax-knock-out, there was an accumulation of doublecortin, calretinin<sup>+</sup>, and neuronal-specific nuclear protein<sup>+</sup> postmitotic neurons, suggesting that Bax-mediated PCD of adult-generated neurons takes place during an early phase of differentiation. The absence of PCD in the adult also influenced the migration and maturation of adult-generated DG neurons. These results suggest that PCD in the adult brain plays a significant role in the regulation of multiple aspects of adult neurogenesis.
Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide
Authors: Takamasa Oono, Yoshinori Fukui, Sadahiko Masuko, Osamu Hashimoto, Takato Ueno, Terukazu Sanui, Ayumi Inayoshi, Mayuko Noda, Michio Sata, Takehiko Sasazuki
Journal: Journal of Clinical Investigation (2001)

Organ-specific autoimmune diseases have been postulated to be the result of T cell response against organ-specific self-peptides bound to MHC molecules. Contrary to this paradigm, we report here that transgenic mice lacking MHC class I expression and expressing an MHC class II I-Ab molecule that presents only a single peptide (Eα52-68) spontaneously develops peripheral nervous system–specific autoimmune disease with many of the histopathological features found in experimental allergic neuritis. Reciprocal bone marrow chimeras produced using susceptible and resistant lines revealed that bone marrow–derived cells determined disease susceptibility. While the expression of the I-Ab–Eα52-68 complex in the periphery was readily detectable in both lines, its expression on thymic dendritic cells responsible for tolerance induction was markedly lower in the susceptible line than in the resistant line. Consistent with this, CD4+ T cells that can be activated by the I-Ab–Eα52-68 complex were found in the susceptible line, but not in the resistant line. Such CD4+ T cells conferred the disease to the resistant line by adoptive transfer, and administration of Ab specific for the I-Ab–Eα52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-Ab–Eα52-68 complex, probably caused by incomplete negative thymocyte selection.
Tricyclic antidepressant poisoning. Reversal of coma, choreoathetosis, and myoclonus by physostigmine
Authors: J. S. Burks
Journal: JAMA (1974)

Two patients with coma, choreoathetoid movements, and myoclonus were found to be poisoned with tricyclic antidepressants. Physostigmine salicylate, a centrally active anticholinergic agent, promptly reversed the neurologic abnormalities. It appears to be the drug of choice in tricyclic antidepressant poisoning as well as in treating classical anticholinergic intoxication. It is relatively safe and can be used as a diagnostic test for suspected poisoning from these agents. These cases also support the cholinergic deficiency/dopaminergic excess hypothesis of chorea. (<i>JAMA</i>230:1405-1407, 1974)
Reply:
Authors: Robert J. Clifford, Kenneth H. Buetow
Journal: Hepatology (2011)

Galichon et al.1 have found that the single-nucleotide polymorphism (SNP) rs2880301 is not a true sequence polymorphism, but rather a pseudovariant originating from a region of homology between the TPTE2 gene and sequences on the Y chromosome. We performed follow-up analysis of this SNP and concur that TPTE2 should no longer be a candidate gene for hepatocellular carcinoma (HCC) disease risk. Based on the observations of Galichon et al., we examined the genomic sequences surrounding the position of rs2880301, which is reported in the National Center for Biotechnology Information (NCBI) dbSNP2 database as an SNP in TPTE2 on chromosome 13.3 We performed a BLAST (Basic Local Alignment Search Tool) analysis similar to Galichon et al. and also showed that the region of homology between chromosomes 13 and Y extends for more than 100 kilobases, with 91.5% identity overall with nucleotide differences reported as SNPs representing differences on the two chromosomes. However, similar analysis of rs2551677, which also distinguishes HCC and cirrhosis in our study,4 confirms that it is a bona fide SNP on chromosome 2. We agree with Galichon et al. of the need to validate results from genome-wide association studies, especially those performed with high-density microarrays. Although genome-wide association studies provide a powerful means to identify disease-associated loci, they should be treated as exploratory. Definitive results depend on the validation of candidate disease-associated variants by independent, detailed investigations such as that performed by Galichon et al. Robert J. Clifford Ph.D.*, Kenneth H. Buetow Ph.D.*, * Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD.
On the External Use of the Solution of the Pernitrate of Mercury in Epithelial Cancer, Lupus Exedens, and the Induration of Chancre
Authors: J. Gay
Journal: BMJ (1862)

with symptoms which were reported to have been those of congestion of the brain.No cough had manifested itself until the day preceding his admission, and his '-ettthing was not affected until the morniing.When admnitted, he was in the first stage of the croupy symptoms; the soft palate wvas coated with exu- dationi.The action of an emetic produced considerable relief to the laryngeal symptoms; but was attended with muchieli depression, although the patient was vigor- -ous, and had presented no indication of failure of streng,th.The laryngeal symptoms, however, soon re- turned; they steadily increased in severity; and the child died on the following day.POST MORTEM EXAMIINATION.A thick coating of false 4nembranie of considerable consistence, and adhering closely, covered each tonsil, and the edges of the velum, and existed in patches on the posterior surface of the soft palate.Tile posterior surface of the velum was quite *free from ulceration; nor did any ulceration appear be- Brts Meia ora.
Regional Enteritis
Authors: Louis Zetzel
Journal: New England Journal of Medicine (1956)

IN the early 1930's, two events provided a much needed stimulus for an awakened interest in the small intestine, that most neglected portion of the digestive tract whose importance in the body economy was in inverse proportion to knowledge of its physiology and function.The development of a technic for rapid intubation of the gut has permitted studies on its secretory, motor and absorptive functions and led to procedures of great practical value in the management of patients with disorders of the small intestine.Similarly, in separating from the heterogeneous group of benign granulomas of the gastrointestinal tract, a clinical . . .
The Columnar Epithelial Cell of the Small Intestine: Digestion and Transport
Authors: Jerry D. Gardner, Michael S. Brown, Leonard Laster
Journal: New England Journal of Medicine (1970)

Cellular DigestionCarbohydratesIn the western diet, carbohydrates are ingested almost entirely in the form of starch and the disaccharides, sucrose and lactose; free glucose accounts for less than 3 per cent of ingested carbohydrate.204 Pancreatic amylase initially attacks α-1,4 glycosidic bonds in the interior of starch molecules, producing oligosaccharides, which it hydrolyzes slowly to maltose and maltotriose.205 The α-1,6 branch points are not attacked, and "limit dextrins" of various sizes, containing glucose molecules surrounding α-1,6 branch points, remain. Pancreatic amylase is found not only in the intestinal lumen but also adsorbed to the lining epithelium,206 , 207 and under some conditions . . .
Erratum
Journal: JNCI Journal of the National Cancer Institute (1994)

“Application of Pharmacokinetically Guided Dose Escalation With Respect to Cell Cycle Phase Specificity,” by E. Fuse, S. Kobayashi, M. Inaba, et al. [J Natl Cancer Inst 86:989-996, 1994 (Issue 13)]. Because of a printer's error, information was omitted from three of the figures: logSS/N =0.149 [Fig. 1]; logSS/N = 1.629 [Fig. 2]; logSS/N [above the numbers 0.190 and 0.078 in Fig. 3]. The Journal regrets the error.